Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof

Abstract

Novel non-steroidal compounds are provided which are useful in treating diseases associated with modulation of the glucocorticoid receptor, and/or AP-1 and/or NF-κB activity including inflammatory and immune diseases, obesity and diabetes having the structure of formula (I):, its enantiomers, diastereomers, or a pharmaceutically-acceptable salt, or hydrate, thereof, wherein the group X is O or (R x )(R y ); is heterocyclo or heteroaryl; E is —N—, —NR 1 —, —O—, —C(═O), —S—, —SO 2 —, or —CR 2 —; F is —N—, —NR 1a , —O—, —C(═O), —S—, —SO 2 —, or —CR 2a —; G is independently N, —NR 1b —, —O—, —C(═O), —S—, —SO 2 — or —CR 2b — provided that the heterocyclic ring formed does not contain a S—S or S—O bond and at least one of E, F and G is a hetero atom; and Ma, R x , R y , R 1 , R 1a , R 1b , R 2 , R 2a , R 2b , R 4 , R 5a , R 6 , R 7 , X, Z a and Z are as defined herein. Also provided are pharmaceutical compositions and methods of treating inflammatory- or immune-associated diseases employing said compounds.

1. A compound according to formula I, 
       
         
           
           
               
               
           
         
       
       its enantiomer, diastereomers, and tautomers, or a pharmaceutically-acceptable salt, or hydrate, thereof, wherein the side chain group: 
       
         
           
           
               
               
           
         
       
       is attached to the benzo ring at the 5- or 6-position; 
       
         
           
           
               
               
           
         
       
       is heterocyclo or heteroaryl;
 E is —CR 2 —; 
 F is selected from —N— and —CR 2a —; 
 G is selected from N and —CR 2b —; 
 X is selected from O and (R x )(R y ); 
 M is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclo, and heteroaryl; 
 M a  is a linker between C and M and is selected from a bond; C 1 -C 5  alkylene; C 1 -C 5  alkylene which includes at any position in the chain a) a nitrogen which is substituted with alkyl, b) an oxygen, c) a sulfur, or d) an SO 2  group; —C(R m     1   )(R m     2   )C(═O)N(R m     3   )—; —C(═O)N(R m     1   )C(R m     2   )(R m     3   )—; —N(R m     3   )C(═O)C(R m     1   )(R m     2   )—; —C(R m     1   )(R m     2   )S(═O) 2 N(R m     3   )—; —S(═O) 2 N(R m     1   )C(R m     2   )(R m     3   )—; and —N(R m     1   )C(═O)N(R m     2   )—; (R m  where R m     1   , R m     2    and R m     3    are the same or different and at each occurrence independently selected from H and C 1 -C 4  alkyl, or R m     1    and R m     2    combine to form a C 3-6  carbocyclic or heterocyclo ring; 
 Q is selected from
 (i) hydrogen, halogen, nitro, cyano, hydroxy, unsubstituted C 1 -C 4  alkyl, and substituted C 1 -C 4  alkyl; or 
 (ii) Q and R 6  are combined with the carbons to which they are attached to form a 3- to 6-membered cycloalkyl or heterocyclo ring; 
 (iii) Q and M-M a  are combined with the carbon to which they are attached to form a 3-7 membered ring optionally containing of 0, 1 or 2 heteroatoms which are the same or different and are independently selected form the group consisting of O, S, SO, SO 2 , and N—R 5b , provided that the heterocyclic ring formed does not contain a S—S or S—O bond, wherein this ring may be optionally substituted with 0, 1 or 2 R 3  groups or carbonyl; 
 
 where X is O, Z is selected from
 (i) alkyl, cycloalkyl, heterocyclo, alkylsulfonyl, aryl, and heteroaryl; and 
 (ii) Z is combined with R 5a  and to the carbon to which they are attached to form a 3-6 membered heterocyclic ring which is optionally substituted with 1-2 R 3  groups or carbonyl; 
 
 or when X═(R x )(R y ), Z is selected from
 (i) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, —C(═O)NR 8 R 9 , —C(═O)R 8 , —C(NCN)NR 8 R 9 , C(═O)OR 8 , —SO 2 R 8 , and —SO 2 NR 8 R 9 ; or 
 (ii) Z is combined with R 5a  to form a 3-6 membered heterocyclic ring which is optionally substituted with 1-2 R 3  or carbonyl; 
 
 Z a  is a linker between N and Z and is selected from a bond; C 1 -C 5  alkylene; C 1 -C 5  alkylene which includes at any position in the chain a) a nitrogen which is substituted with alkyl, b) an oxygen, c) a sulfur, or d) an SO 2  group; —C(R z     1   )(R z     2   )C(═O)N(R z     3   )—; —C(═O)N(R z     1   )C(R z     2   )(R z     3   )—; —C(R z     1   )(R z     2   )S(═O) 2 N(R z     3   )—; and —S(═O) 2 N(R z     1   )C(R z     2   )(R z     3   )—; where R z     1   , R z     2    and R z     3    at each occurrence are independently selected from H and C 1 -C 4  alkyl; 
 R 1 , R 1a , R 1b , R x  and R y  are the same or different and at each occurrence are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclo; 
 R 2 , R 2a  and R 2b  are the same or different and at each occurrence are independently selected from
 (i) hydrogen, halogen, alkyl, alkenyl, alkynyl, nitro, cyano, —OR 10 , —NR 10 R 11 , —C(═O)R 10 , —CO 2 R 10 , —C(═O)NR 10 R 11 , —O—C(═O)R 10 , —NR 10 C(═O)R 11 , —NR 10 C(O)OR 11 , —NR 10 C(S)OR 11 , —S(O) p R 12 , —NR 8 SO 2 R 12 , —SO 2 NR 10 R 11 , cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclo, aryl, and heteroaryl; or 
 (ii) two R 2 , R 2a  and R 2b  groups that are located on adjacent carbon atoms may be taken together with the carbons to which they are attached to form a fused ring; 
 
 R 3  at each occurrence is independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cyano, —OR 13 , —NR 13 R 14 , —C(═O)R 13 , —CO 2 R 13 , —C(═O)NR 13 R 14 , —O—C(═O)R 13 , —NR 13 C(═O)R 14 , —NR 13 C(O)OR 14 , —NR 13 C(S)OR 14 , —S(O) p R 15 , —NR 13 SO 2 R 15 , —SO 2 NR 13 R 14 , cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclo, aryl, and heteroaryl; 
 R 4  is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cyano, and C 1 -C 4  alkoxy; 
 R 5a  is selected from hydrogen and alkyl; and 
 R 6  is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, nitro, cyano, —OR 16 , —NR 16 R 17 , —C(═O)R 17 , —CO 2 R 17 , —C(═O)NR 16 R 17 , —O—C(═O)R 16 , —NR 16 C(═O)R 17 , —NR 16 C(═O)OR 17 , —NR 16 C(═S)OR 17 , —S(O) p R 18 , —NR 16 SO 2 R 18 , —SO 2 NR 16 R 17 , cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroaryl; 
 R 7  is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, nitro, cyano, OR 19 , NR 19 R 20 , —C(═O)R 19 , —CO 2 R 19 , —C(═O)NR 19 R 20 , —O—C(═O)R 19 , —NR 19 C(═O)R 20 , —NR 19 C(═O)OR 20 , —NR 19 C(═S)OR 20 , —S(O) p R 21 , —NR 19 SO 2 R 21 , —SO 2 NR 19 R 20 , cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclo, aryl, and heteroaryl; 
 or R 6  and R 7  are taken together with the carbon to which they are attached to form a cycloalkyl, cycloalkenyl, or heterocyclo ring; 
 R 5b , R 8 , R 9 , R 10 , R 11 , R 13 , R 13a , R 14 , R 16 , R 17 , R 19  and R 20  are the same or different and at each occurrence are independently selected from
 (i) hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclo; or 
 (ii) with respect to Z, R 8  taken together with R 9 , and/or with respect to R 3  and R 6 , R 15  is taken together with R 16 , and/or with respect to R 6  and R 7 , R 18  is taken together with R 19 , and/or with respect to R 7 , R 20  is taken together with R 21  to form a 4- to 6-membered heteroaryl or heterocyclo ring; 
 
 R 12 , R 15 , R 18  and R 21  are the same or different and are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclo; and 
 p is 0, 1 or 2, 
 
       provided that where the ring system 
       
         
           
           
               
               
           
         
       
       and Q and M a -M are independently H, CH 3  or C 2 H 5 , then Z a —Z is other than 
       
         
           
           
               
               
           
         
       
       where G 1  is a heteroaryl, acetyl, carbamoyl, or —C(═S)CH 3  or —C(═S)C 2 H 5 . 
     
     
       2. The compound according to  claim 1  having the structure 
       
         
           
           
               
               
           
         
       
     
     
       3. The compound according to  claim 1  having the structure 
       
         
           
           
               
               
           
         
       
     
     
       4. The compound as defined in  claim 1  where in 
       
         
           
           
               
               
           
         
         E is CR 2 ; 
         F is N; and 
         G is CR 2b ; 
         X is (R x )(R y ) where R x  and R y  are the same or different and are independently selected from H and alkyl; or 
         X is O; 
         R 6  is alkyl or H; 
         R 7  is alkyl or H; 
         M is aryl or H; 
         M a  is a bond; 
         Q is H; or 
         E is CR 2  where R 2  is H, aryl or alkyl;
 F is N or CR 2a ; 
 G is CR 2b  where 
 R 2b  is selected from haloaryl, halo, cyanoaryl, H, dihaloaryl, hydroxyalkylaryl and heteroaryl, or 
 G is N; 
 where X is (R x )(R y ) then Z is selected from cycloalkyl, heteroaryl, aryl, heterocyclo, —C(═O)NR 8 R 9 , —C(═O)R 8 , —C(NCN)NR 8 R 9 , and —C(═O)OR 8 ; 
 where X is O then Z is selected from heteroaryl, cycloalkyl, aryl, heterocyclo, and alkyl; and 
 Z a  is a bond. 
 
       
     
     
       5. The compound as defined in  claim 1  wherein 
       
         
           
           
               
               
           
         
       
       is selected from 
       
         
           
           
               
               
           
         
       
     
     
       6. The compound as defined in  claim 1  wherein 
       
         
           
           
               
               
           
         
       
       where R 2  is selected from aryl, H and alkyl,
 R 2b  is selected from H, halogen, aryl, and heteroaryl; 
 and R 4  is selected from H and methyl; or 
 
       
         
           
           
               
               
           
         
       
       where R 2  is selected from H, alkyl and aryl;
 and R 4  is selected from H and methyl. 
 
     
     
       7. A compound as defined in  claim 1  wherein:
 Z is selected from 
 
       
         
           
           
               
               
           
         
         R m  and R n  are the same or different and at each occurrence are independently selected from hydrogen, halogen, cycloalkyl, cyano, —CO 2 R c , —NR a R b , —C(═O)R c , —C(O)N(R a )(R b ), OR c , alkyl, substituted alkyl, aryl, heteroaryl and heterocyclo; 
         or R m  and R n  combine to form a 5-, 6- or 7-membered carbocyclic, aryl, heteroaryl or cycloheteroalkyl ring which contains 0, 1, 2 or 3 hetero atoms which can be N, O, or S; 
         R a  and R b  are the same or different and at each occurrence are independently selected from (1) hydrogen, alkyl, C(═O)alkyl, CO 2 (alkyl), SO 2 alkyl, alkenyl, alkynyl, amino, aryl, heteroaryl, cycloalkenyl, heterocyclo, and cycloalkyl, provided R a  and R b  are not both alkoxy, amino, or substituted amino, or (2) where possible R a  is taken together with R b  to form a heteroaryl or heterocyclo ring; and 
         R c  is selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amino, heteroaryl, heterocyclo, cycloalkyl, and aryl. 
       
     
     
       8. The compound as defined in  claim 4  wherein G is N or G is CR 2b  and R 2b  is 
       
         
           
           
               
               
           
         
         E is CR 2  and R 2  is 
       
       
         
           
           
               
               
           
         
       
       H or CH 3 ;
 F is N; and 
 R 6  is CH 3  or H; 
 R 7  is CH 3  or H; and 
 M-M a  is 
 
       
         
           
           
               
               
           
         
       
       or H. 
     
     
       9. The compound as defined in  claim 5  wherein Z is 
       
         
           
           
               
               
           
         
       
     
     
       10. The compound as defined in  claim 1  wherein 
       
         
           
           
               
               
           
         
       
     
     
       11. The compound as defined in  claim 1  having the structure 
       
         
           
           
               
               
           
         
       
       where
 G is N or CR 2b ; 
 R 2  is H, CH 3  or 
 
       
         
           
           
               
               
           
         
         R 2b  is Br, 
       
       
         
           
           
               
               
           
         
         R 4  is H or CH 3 ; 
         R 6  is H or CH 3 ; 
         R 7  is H or CH 3 ; 
         Q is 
       
       
         
           
           
               
               
           
         
         M is H; 
         M a  is a bond; 
         R 5a  is H; 
         Z is 
       
       
         
           
           
               
               
           
         
         R x  is H; 
         R y  is H; and 
         Z a  is a bond; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       12. The compound as defined in  claim 1  having the structure 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       13. A pharmaceutical composition comprising a compound as defined in  claim 1  and a pharmaceutically acceptable carrier therefor. 
     
     
       14. A pharmaceutical combination comprising a compound as defined in  claim 1  and an antidiabetic agent, an anti-obesity agent, an antihypertensive agent, and/or an antiosteoporosis agent, wherein the antidiabetic agent is 1, 2, 3 or more of a metformin, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ agonist, a PPAR α/γ dual agonist, an SGLT2 inhibitor, a DP4 inhibitor, an aP2 inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and/or a meglitinide, wherein the anti-obesity agent is a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor agonist, an aP2 inhibitor and/or an anorectic agent, wherein the antihypertensive agent is an ACE inhibitor, angiotensin II receptor antagonist, NEP/ACE inhibitor, calcium channel blocker and/or β-adrenergic blocker, and the antiosteoporosis agent is parathyroid hormone or a biphosphonate.